The present invention relates to a compound, which have antagonism effect on muscarinic receptor and can be useful as anticholinergic medicaments, its prodrug and pharmaceutically acceptable salt thereof, and their use. Antagonists against muscarinic receptor can be used, for example, as mydriatic medicament, anticonvulsant, parkinsonian remedy, antasthmatic, peptic ulcer remedy, secretagogue and motofacient for gastric and duodenal ulcer, intestinum hypersensitivity remedy, pollakiuria remedy, urinary incontinence remedy, antiarrhythmic medicament, esophageal achalasia remedy, chronic obstructive tracheal disease remedy and so on.
The quinazolinone derivatives having subneural, anti-inflammatory and analgesic action are described in Japanese Unexanined Patent Publication No. sho47-14183, the quinazolinone derivatives having an effect of inhibiting central nervous system are described in French Patent No. 2,027,023, and the quinazolinone derivatives having an effect of preventing overload of calcium ions are described in Japanese Unexamined Patent Publication No. hei7-41465, respectively. However, they do not refer to the use of anticholinergic medicament, especially urinary incontinence and pollakiuria remedy.
The subject of the present invention is to provide antagonists against muscarinic receptor which is useful as anticholinergic medicament.
The present inventors have earnestly studied for solving the above problem, found that the compounds given by general formula (1) below, their prodrugs and pharmaceutically acceptable salts thereof have antagonism effect on muscarinic receptor, and now completed the present invention. Namely, the present invention relates to the following [11] to [15]:
[1] An anticholinergic medicament comprising a compound given by general formula (1): 
[wherein T represents oxygen or sulfur atom, and Y represents alkyl, cycloalkyl, cycloalkylalkyl, phenyl, substituted phenyl, aralkyl, substituted aralkyl, heteroaryl or substituted heteroaryl group. Ring W represents benzene, 5-6 membered heteroaromatic, 5-10 membered cycloalkene or 5-10 membered cycloalkane ring. R1 and R2 represent independently hydrogen atom, lower alkyl group, halogen atom, cyano, trifluoromethyl, nitro, amino, substituted amino, hydroxy, lower alkoxy, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl group. R3 represents hydrogen atom, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, aralkyl or substituted aralkyl group.
Z represents a group given by formula: 
{wherein A1 and A2 represent independently hydrogen atom, alkyl, substituted alkyl, cycloalkyl, saturated heterocyclic, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, substituted aralkyl, heteroarylalkyl, substituted heteroarylalkyl or xe2x80x94CH2R4 group (wherein R4 represents alkenyl or alkynyl group), or A1 and A2 are combined together and form heterocyclic ring. G represents straight chain alkylene having 1-6 of the carbon number, branched alkylene having 2-8 of the carbon number, a group given by formula: 
(wherein p and m represent independently 0, 1 or 2 and D represents cycloalkane ring)} or 
{wherein n represents 0, 1 or 2, ring E represents 4-8 membered saturated heterocyclic ring containing nitrogen atom(s), and A3 represents hydrogen atom, alkyl, substituted alkyl, cycloalkyl, saturated heterocyclic, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, substituted aralkyl, heteroarylalkyl, substituted heteroarylalkyl or xe2x80x94CH2R4 group (wherein R4 represents alkenyl or alkynyl group), or forms bicyclo ring together with ring E}], its prodrug or pharmaceutically acceptable salt thereof as an active ingredient.
[2] An anticholinergic medicament described in [1], wherein ring W represents 5-6 membered heteroaromatic, 5-10 membered cycloalkene or 5-10 membered cycloalkane ring.
[3] An anticholinergic medicament described in [1], wherein ring W represents benzene ring and Z represents a group given by formula: 
[4] An anticholinergic medicament described in [1], wherein Z represents a group given by formula: 
[5] An anticholinergic medicament described in [4], wherein ring W represents benzene or pyridine ring.
[6] An anticholinergic medicament described in [5], wherein ring W represents benzene ring.
[7] An anticholinergic medicament described in [6], wherein Y represents phenyl or substituted phenyl group.
[8] An anticholinergic medicament described in [4], wherein ring W represents benzene or pyridine ring and Z represents a group given by formula: 
(wherein A4 represents phenyl, substituted phenyl, cycloalkyl or cycloalkenyl group).
[9] An anticholinergic medicament described in [8], wherein A4 represents cycloalkyl or cycloalkenyl group.
[10] An anticholinergic medicament described in [8], wherein A4 represents phenyl or substituted phenyl group.
[11] An anticholinergic medicament described in [8], wherein A4 represents substituted phenyl group and said substituent is cyano, alkoxyalkyl, alkanoylamino, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group.
[12] An anticholinergic medicament described in any of [1]-[11], wherein the medicament is urinary incontinence or pollakiuria remedy.
[13] A compound given by general formula (1): 
[wherein T represents oxygen or sulfur atom, and Y represents alkyl, cycloalkyl, cycloalkylalkyl, phenyl, substituted phenyl, aralkyl, substituted aralkyl, heteroaryl or substituted heteroaryl group. Ring W represents benzene or pyridine ring. R1 and R2 represent independently hydrogen atom, lower alkyl group, halogen atom, cyano, trifluoromethyl, nitro, amino, substituted amino, hydroxy, lower alkoxy, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl group. R3 represents hydrogen atom, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aralkyl or substituted aralkyl group. Z represents a group given by formula: 
(wherein A4 represents phenyl group substituted by alkoxyalkyl group), its prodrug or pharmaceutically acceptable salt thereof.
[14] A compound given by general formula (1a): 
[wherein T represents oxygen or sulfur atom, and Y represents alkyl, cycloalkyl, cycloalkylalkyl, phenyl, substituted phenyl, aralkyl, substituted aralkyl, heteroaryl or substituted heteroaryl group. Ring W represents benzene, 5-6 membered heteroaromatic, 5-10 membered cycloalkene or 5-10 membered cycloalkane ring. R1 and R2 represent independently hydrogen atom, lower alkyl group, halogen atom, cyano, trifluoromethyl, nitro, amino, substituted amino, hydroxy, lower alkoxy, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl group. R31 represents alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aralkyl or substituted aralkyl group. Z represents a group given by formula: 
{wherein A1 and A2 represent independently hydrogen atom, alkyl, substituted alkyl, cycloalkyl, saturated heterocyclic, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, substituted aralkyl, heteroarylalkyl, substituted heteroarylalkyl or xe2x80x94CH2R4 group (wherein R4 represents alkenyl or alkynyl group), or A1 and A2 are combined together and form heterocyclic ring. G represents straight chain alkylene having 1-6 of the carbon number, branched alkylene having 1-8 of the carbon number, a group given by formula: 
(wherein p and m represent independently 0, 1 or 2 and D represents cycloalkane ring)} or formula: 
{wherein n represents 0, 1 or 2, ring E represents 4-8 membered saturated heterocyclic ring containing nitrogen atom(s), and A3 represents hydrogen atom, alkyl, substituted alkyl, cycloalkyl, saturated heterocyclic, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, substituted aralkyl, heteroarylalkyl, substituted heteroarylalkyl or xe2x80x94CH2R4 group (wherein R4 represents alkenyl or alkynyl group), or forms bicyclo ring together with ring E}], its prodrug or pharmaceutically acceptable salt thereof
[15] A compound described in [14], wherein Z represents a group given by formula: 
its prodrug or pharmaceutically acceptable salt thereof.
As the compounds given by general formula (1a) are a part of the compounds given by general formula (1), the explanation of the compounds given by general formula (1) should be construed as the explanation of the compounds given by general formula (1a).
Further, the compounds given by general formula (1), its prodrug or pharmaceutically acceptable salt thereof may be referred as to the present compound in this description.
A part of the compounds used in the present invention, namely, the presnt compounds, wherein ring W is benzene ring and Z is a group given by formula: 
(wherein G, A1 and A2 mean as defined above) is known as compounds having subneural, anti-inflammatory and analgesic action in Japanese Unexamined Patent Publication No. sho47-14183, and compounds having an effect of inhibiting central nervous system in French Patent No. 2,027,023. Further, the present compounds, wherein R3 is hydrogen atom, are known as medicament for preventing overload of calcium ions in Japanese Unexamined Patent Publication No. hei7-41465. However, in these publications, use of anticholinergic medicament, especially urinary incontinence and pollakiuria remedy is not described.
The various groups in the present invention are explained in detail below. The explanation for each group is also applied to the parts of the other substituents unless specifically noticed.
Typical 5-6 membered heteroaromatic ring for ring W is exemplified by heteroaromatic rings having 0, 1 or 2 nitrogen atom(s), 0 or 1 sulfur atom, and 0 or 1 oxygen atom. The examples are more typically as follows: 
preferably the groups below: 
Typical 5-10 membered cycloalkene or cycloalkane ring for ring W is exemplified as follows: 
(wherein u and v independently represent 0 or an integer of 1 to 5, and u+v represents an integer of 1 to 6, further bold and dotted lines in the formulae represent relative configuration at adjacent carbon atoms of bridge head and do not represent a specific optical isomer, that is the same as the structural formulae hereinafter.), preferably the groups below: 
Typical straight chain alkylene having 1-6 of the carbon number for G is exemplified by methylene, dimethylene, trimethylene and tetramethylene, and typical branched alkylene having 2-8 of the carbon number is as follows: 
Examples of the cycloalkane ring for D include cycloalkane ring having 3-8 of the carbon number, typically cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane.
Preferable groups of G are exemplified by dimethylene, trimethylene, tetramethylene and the groups below: 
Examples of the alkyl group include straight chain or branched alkyl group having 1-8 of the carbon number, typically methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, 2-methylpropyl, 1,1-dimethylethyl, 3-pentyl, 3-hexyl, 4-heptyl and 4-octyl. Preferable group is exemplified by 2-propyl, butyl, 2-butyl, 2-methylpropyl, 3-pentyl and 3-hexyl for Y, and straight chain or branched alkyl group having 1-4 of the carbon number such as methyl, ethyl, propyl and 2-propyl for A1 and A2.
Examples of the acyl group include alkanoyl and aroyl group.
Examples of the alkanoyl group include one connected with alkyl group at either bond of the carbonyl group.
Examples of the aroyl group include one connected with aryl group at either bond of the carbonyl group.
Examples of the cycloalkyl group include cycloalkyl group having 3-8 carbon number, typically cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
Examples of the cycloalkylalkyl group include cycloalkylalkyl group having 10 or less of the carbon number, typically cyclopropylmethyl, 2-cyclopentylethyl, cyclohexylmethyl, 3-cyclohexylpropyl and 4-cyclohexylbutyl.
Examples of the cycloalkenylalkyl group include cycloalkenylalkyl group having 10 or less of the carbon number, typically 4-cyclohexenylmethyl, 4-cyclopentenylmethyl and 4-(4-cyclohexyenyl)butyl.
Examples of the alkenyl group include alkenyl group having 2-6 of the carbon number, typically vinyl, allyl, 1-propenyl, 1-butenyl, 2-pentenyl and 5-hexyenyl, preferably, allyl, 1-propenyl and 1-butenyl group.
Examples of the alkynyl group include alkynyl group having 2-6 of the carbon number, typically ethynyl, propargyl, 2-butynyl and 3-pentynyl, preferably ethynyl and propargyl.
Examples of the aralkyl group include aralkyl group having 12 or less of the carbon number, typically benzyl, 1-phenylethyl, 2-phenylethyl and 2-naphthylmethyl. Preferable group is benzyl group for A3.
Examples of the heteroaryl group include 5-6 membered ring group containing 1 or 2 nitrogen atom(s), 5-6 membered ring group containing 1 or 2 nitrogen atom(s) and one oxygen or sulfur atom, and 5-6 membered ring group containing one oxygen or sulfur atom, typically 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-oxadiazolyl, 2-imidazolyl, 2-thiazolyl, 3-isothiazolyl, 2-oxazolyl, 3-isoxazolyl, 2-furyl and 3-pyrrolyl.
Examples of the heteroaryl group for the heteroarylalkyl group include 5-6 membered ring group containing 1-4 nitrogen atom(s), and 5-6 membered ring group containing 1-2 nitrogen atom(s) and one oxygen or sulfur atom. Typical heteroarylalkyl group is exemplified by 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 1-(2-pyridyl)ethyl, 2-(2-pyridyl)ethyl, 2-thienylmethyl, 3-thienylmethyl, 3-oxadiazolylmethyl, 2-imidazolylmethyl, 2-thiazolylmethyl, 3-isothiazolylmethyl, 2-oxazolylmethyl, 3-isoxazolylmethyl, 2-furylmethyl, 3-furylmethyl and 2-pyrrolylmethyl.
Examples of the saturated heterocyclic group include the saturated heterocyclic group consisting of one hetero atom such as oxygen and sulfur atom and 3-5 carbon atoms, typically tetrahydropyran-4-yl, tetrahydrofuran-3-yl and tetrahydrothiophen-3-yl.
Examples of the heterocyclic ring formed by A1 and A2 bonded each other include 5-7 membered ring containing 1-2 nitrogen atom(s), or saturated or unsaturated 5-7 membered ring containing one nitrogen atom and one oxygen atom, typically pyrrolidine, piperidine, homopiperidine, piperazine, homopiperazine, morpholine, imidazole and pyrazole.
Examples of the 4-8 membered saturated heterocyclic ring containing nitrogen atom for ring E include ring containing 1 or 2 nitrogen atoms and 0 or 1 oxygen atom, typically pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-2-yl, homopiperidin-3-yl, homopiperidin-4-yl and morpholin-2-yl. When n is 0, piperidin-4-yl is preferable.
Examples of the bicyclo ring formed by ring E and A3 include quinuclidin-3-yl and quinuclidin-4-yl.
Examples of the lower alkyl group include straight chain or branched alkyl group having 4 or less of the carbon number, typically methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, 2-methylpropyl and 1,1-dimethylethyl.
Examples of the halogen atom include fluorine, chlorine, bromine and iodine atom.
Examples of the lower alkoxy group include straight chain or branched alkoxy group having 4 or less of the carbon number, typically methoxy, ethoxy, propoxy, 2-propoxy, butoxy and 1,1-dimethylethoxy.
Examples of the lower alkylthio group include straight chain or branched alkylthio group having 4 or less of the carbon number, typically methylthio, ethylthio, 2-propylthio and butylthio.
Examples of the aryl group include the group having 10 or less of the carbon number, typically phenyl, 1-naphthyl and 2-naphthyl.
Examples of the lower alkylsulfinyl group include straight chain or branched alkylsulfinyl group having 4 or less of the carbon number, typically methylsulfinyl, ethylsulfinyl, propylsulfinyl, 2-propylsulfinyl and butylsulfinyl.
Examples of the lower alkylsulfonyl group include straight chain or branched alkylsulfonyl group having 4 or less of the carbon number, typically methylsulfonyl, ethylsulfonyl, propylsulfonyl, 2-propylsulfonyl and butylsulfonyl.
Examples of the substituent for the substituted amino group include alkyl or xe2x80x94CH2R4xe2x80x94 group (wherein R4 represents alkenyl or alkynyl group), and the substituent may be one or two which are the same or different from each other. Preferable substituted amino groups are exemplified by methylamino, ethylamino, allylamino, propargylamino, propylamino, 2-propylamino, butylamino, N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino and N,N-diallylamino.
Examples of the substituent for the substituted aryl, substituted phenyl, substituted aralkyl, substituted benzyl, substituted heteroaryl and substituted heteroarylalkyl group include lower alkyl, lower alkoxy, methylenedioxy group, halogen atom, cyano, trifluoromethyl, nitro, hydroxy, alkanoyloxy, carboxyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido group, a group of formula xe2x80x94NR6R7 (wherein R6 and R7 independently represent hydrogen atom, alkyl, xe2x80x94CH2R4 (wherein R4 represents the meaning defined above), di- lower alkylamino-substituted alkyl, alkoxy-substituted alkyl, cycloalkyl, alkoxycarbonyl, heteroarylmethyl or aralkyl group, or R6 and R7 are combined together to form saturated cyclic amino group having 4 to 8 carbons, which constitute the ring, and further optionally one xe2x80x94NR8xe2x80x94 (R8 represents hydrogen atom, lower alkyl, phenyl, lower alkoxycarbonyl or benzyl group) or one oxygen atom, with the nitrogen atom to which R6 and R7 are bonded), xe2x80x94C(xe2x95x90O)NR6R7 (R6 and R7 represent the same meanings defined above), xe2x80x94NR5C(xe2x95x90O)Q1 (R5 represents hydrogen atom or lower alkyl group, and Q1 represents alkyl, alkenyl, alkynyl, cycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl group), or E1xe2x80x94M1xe2x80x94E2xe2x80x94Q2 {E1 represents bond or divalent hydrocarbyl group having 1-4 of the carbon number, M1 represents bond, oxygen or sulfur atom, or xe2x80x94NR5xe2x80x94 (R5 represents the same meaning defined above). E2 represents divalent hydrocarbyl group, which may contains unsaturated bond, having 1-6 of the carbon number, provided that E1 and M1 are combined to form one bond when both of E1 and M1 represent bond. Q2 represents hydrogen atom, hydroxy, carboxyl, alkoxycarbonyl, alkanoyloxy, benzyloxycarbonyl group, halogen atom, cyano, benzyloxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkyl-substituted or unsubstituted benzenesulfonyloxy (e.g. p-toluenesulfonyloxy), alkoxycarbonylamino, alkylsulfonamido, phthalimido, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl group, a group of formula xe2x80x94NR6R7 (R6 and R7 represent the same meaning defined above), xe2x80x94C(xe2x95x90O)NR6R7 (R6 and R7 represent the same meanings defined above), xe2x80x94NR5C(xe2x95x90O)Q1 (R5 and Q1 represent the same meanings defined above)}. Examples of the substituent for substituted aryl, substituted aralkyl, substituted heteroaryl and substituted heteroarylalkyl group of Q1 and Q2 include lower alkyl group, halogen atom, trifluoromethyl and cyano group, and the substituents may be plural and the same or different from each other. Further, the lower means that the alkyl part of said group is lower alkyl, and examples of the lower alkyl include the alkyl having 1-4 of the carbon number such as methyl, ethyl, propyl, 2-propyl and butyl.
The saturated cyclic amino groups constituted by 4 to 8 carbons and further optionally one xe2x80x94NR8xe2x80x94 (R8 represents the same meaning defined above) or one oxygen atom, which R6 and R7 are combined together to form with the nitrogen atom to which R6 and R7 are bonded, are typically exemplified by 1-pyrrolidinyl, piperidino, 1-homopiperidinyl, morpholino and 4-methylpiperazin-1-yl.
The divalent hydrocarbyl groups having 1-4 of the carbon number for E1 are exemplified by typically straight chain or branched alkylene group, more typically methylene, ethylene, propylene, trimethylene, tetramethylene and 1-ethylethylene.
Examples of the divalent hydrocarbyl group, which may contain unsaturated bond, having 1-6 of the carbon number for E2 include straight chain or branched alkylene group such as methylene, ethylene, trimethylene, tetramethylene and 1-ethylethylene; straight chain or branched alkenylene group such as vinylene, 1-propenylene, 2-butenylene and 4-methyl-2-pentenylene; straight chain or branched alkynylene group such as ethynylene, 2-propynylene, 2-butynylene and 4-methyl-2-pentynylene; and o-, m- and p-phenylene group.
Examples of the substituent for substituted alkyl, substituted alkenyl, substituted alkynyl and substituted cycloalkyl include hydroxy, amino, lower alkylamino, di-lower alkylamino, carboxyl, lower alkoxycarbonyl, benzyloxycarbonyl group, halogen atom, cyano, benzyloxy, alkoxy, lower alkanoyloxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, alkanoylamino, lower alkoxycarbonylamino and lower alkylsulfonamido group, herein lower means that the alkyl part of said group is lower alkyl. Such lower alkyl is exemplified by the alkyl group having 1-4 of the carbon number such as methyl, ethyl, propyl, 2-propyl and butyl.
Prodrugs can be exemplified by the compounds reproducing the compound given by formula (1) or (1a). Examples for the compounds having a carboxyl group include the compounds having alkoxycarbonyl, alkylthiocarbonyl or alkylaminocarbonyl group in place of the carboxyl group. Examples for the compounds having an amino group include the compounds having alkanoylamino given by alkanoyl substitution, alkoxycarbonylamino given by alkoxycarbonyl substitution or acyloxymethylamino in place of the amino group, and hydroxylamine compounds. Examples for the compounds having a hydroxy group include the compounds having acyloxy given by acyl substitution, phosphate ester compounds and acyloxymethyoxy compounds. The alkyl part of the group for preparing these prodrugs may be the above-mentioned alkyl group that may be substituted by alkoxy group having 1-6 of the carbon number and so on. Preferable examples for the compound having alkoxycarbonyl in place of carboxyl group include lower (e.g. 1-6 of the carbon number) alkoxycarbonyl such as methoxycarbonyl and ethoxycarbonyl and lower (e.g. 1-6 of the carbon number) alkoxycarbonyl substituted by alkoxy group such as methoxymethoxycarbonyl, ethoxymethoxycarbonyl, 2-methoxyethoxycarbonyl, 2-methoxyethoxymethoxycarbonyl and pivaloylmethoxycarbonyl.
Pharmaceutically acceptable salts can be exemplified by acid addition salts and quarternary ammonium salts.
Examples of the acid for the acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid and sulfuric acid, and organic acids such as acetic acid, oxalic acid, citric acid, malic acid, tartaric acid, fumaric acid, maleic acid and methanesulfonic acid.
Examples of the quarternary ammonium salts include the quarternary ammonium salts prepared by the reaction with an alkylating agent of formula:
R9xe2x80x94G1
(wherein R9 represents lower alkyl group and G1 represents a leaving group), and optionally changing an anion to another physiologically acceptable anion. Preferable lower alkyl groups are exemplified by methyl and ethyl group. Examples of the physiologically acceptable anion include halogen ion, sulfate, phosphate, nitrate, acetate, citrate, fumarate, succinate and so on. Preferable leaving groups are exemplified by chlorine, bromine and iodine atom.
The present compounds have one or more asymmetric carbon atoms and there exist stereoisomers. The present compounds contain a mixture of each isomer and isolated isomer.
The present compounds may be their anhydrides or solvate such as hydrate.
In the present compounds, the compounds wherein the ring W represents benzene or pyridine ring, especially the compounds among them, wherein Z represents formula: 
are selective in the muscarinic part of the smooth muscle rather than muscarinic part of the heart. Therefore, they are useful for curing a disease relating to alteration and/or tension of exercise of smooth muscle observed in intestine, trachea and bladder in particular. These diseases include intestinum hypersensitivity, urinary incontinence, pollakiuria, esophageal achalasia and chronic obstructive tracheal disease. Further, among the above-mentioned compounds, the compounds wherein A3 represents cycloalkylmethyl, cycloalkenylmethyl, benzyl or substituted benzyl group are especially useful as pollakiuria and/or urinary incontinence remedy.
When the above-mentioned compounds given by formula (1), their acid addition salts or quarternary ammonium salts are utilized as anticholinergic. medicament, they can be administered parenterally or orally. Namely, liquid formulations such as solution, emulsion and suspension may applied as injections, to which buffer, dissolving assistant, isotonic agent and so on may be optionally added. They can also be administered via rectum as suppository. These formulations are prepared by mixing a usual carrier, excipient, binder, stabilizer and so on with the active ingredient according to general methods. Further, usual preparations such as tablet, capsule, syrup, suspension and so on may be administered orally. The dose and frequency vary depending on the symptom, age, body weight, type of formulation and so on. In case of injecting administration, they may be applied in general, in an amount of 0.1 to 100 mg at once or in several times for adult. They may also be administrated by intravenous drip. In case of oral administration, an amount of 0.1 to 1000 mg, preferably 1 to 400 mg, may be applied once or in several times, for example 2 to 4 times, a day.
In the compounds given by general formula (1), the compound wherein R3 represents hydrogen atom can be prepared by the methods described in U.S. Pat. No. 5,556,860 or their variations. Further, the compound except the compounds wherein R3 represents hydrogen atom can be prepared by the method below: 
wherein ring W, Y, Z, T, R1 and R2 represent the meanings as defined above. R31 means the definition of R3 except hydrogen atom. Y1, Z1, R11, R21 and R32 represent the same groups as Y, Z, R1, R2 and R31 respectively, provided that amino, alkylamino, hydroxy, carboxyl and the other reactive groups are protected when these substituents are contained. G2 represents a leaving group.
The compound given by general formula (4) can be prepared by the reaction of the compound given by general formula (2) with an alkylating agent given by general formula (3) in a solvent, and optionally deprotection. The reaction may be usually carried out in a solvent at 0-100xc2x0 C., preferably room temperature to 70xc2x0 C. in the presence of a base. Examples of the solvent include ethers such as tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene and toluene; ketones such as acetone and 2-butanone; and dimethylformamide. Examples of the base include sodium hydride, potassium carbonate, sodium carbonate and triethylamine. In case of utilizing potassium carbonate or sodium carbonate, an addition of sodium iodide or potassium iodide may raise the yield. The leaving group given by G2 is usually halogen atom such as chlorine, bromine and iodine and aromatic sulfonyloxy group such as p-toluenesulfonyloxy group. Examples of the protecting group for amino, alkylamino, hydroxy, carboxyl group and so on include usual protecting groups (e.g. benzyl and acetyl group for protecting hydroxy group, benzyl group for protecting amino group, etc.) used in organic synthesis field in general. These groups can be derived and eliminated by usual methods. (cf. Protective Groups in Organic Synthesis, 2nd ed., John Wiley and Sons, Inc., New York)